ABSTRACT - PROJECT 2 High-dose chemoradiotherapy conditioning before allogeneic hematopoietic cell transplantation (HCT) is potentially curative for patients with advanced myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), or myelodysplastic syndrome (MDS) who have failed conventional chemotherapy; however, allogeneic HCT produces a 5-year survival rate of only 20-30%.as a result of non-relapse mortality and, especially, relapse. Prior studies in younger patients have shown that increasing the dose of total body irradiation prior to HCT significantly reduces the relapse rate but increases regimen-related toxicity, negating the advantage of the lower relapse rate. Moreover, most patients with AML or MDS are older than 60 years and unable to tolerate high-dose conditioning. As an alternative to high-dose conditioning, we have explored the use of beta-emitters - iodine-131 and yttrium-90 conjugated with our anti-CD45 monoclonal antibody - as an adjunct strategy to deliver targeted radiation to hematolymphoid tissues and disease sites while minimizing toxicity to normal organs. However, the long path length, long half-life, and relatively low energy of these radioisotopes may not provide enough targeted radiation and still have off-target effects. An attractive alternative to the beta-emitters is the use of alpha-emitting radionuclides. The short path length, very high energy, high cytotoxicity of alpha-emissions, and short half-life may generate effective tumor cell kill while avoiding early toxicities as well as late effects, such as secondary cancers, associated with conventional systemic conditioning agents including beta-emitters. We propose the use of the alpha-emitter astatine-211 (211At), which is short-lived and provides high-energy radiation, conjugated to our anti-CD45 antibody as part of an HCT conditioning regimen for patients with advanced AML, ALL or high-risk MDS. Specific Aim 1 will investigate the 211At-labeled anti-CD45 antibody as an adjunct to a well-tolerated reduced-intensity conditioning regimen for human leukocyte antigen (HLA)- matched related or unrelated HCT. Furthermore, there remains a critical need to extend the option of HCT as potential therapy of hematologic malignancies to patients who do not have a readily available HLA-matched donor, a problem especially acute for patients in ethnic minority groups. In these cases, donors would be HLA- haploidentical relatives. The current HLA-haploidentical HCT conditioning regimen, while well tolerated, has a relapse rate of 47% at 1 year. Therefore, Specific Aim 2 proposes the addition of 211At-labeled anti-CD45 antibody to the conditioning regimen for HLA-haploidentical HCT to improve disease control for advanced AML, ALL, and high-risk MDS in patients without substantially increasing the toxicity. We believe that our extensive preclinical experience using alpha-emitters combined with our preclinical and clinical experience with beta- emitters predicts a high likelihood of success.